Abstract:

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by
amyloid-β (Aβ) plaque formation, tau pathology, neurodegeneration and inflammatory processes.
Monocytes are involved in inflammation in AD and are recruited to the diseased brain. Recently it has
been shown that aberrant epigenetic processes including acetylation are associated with the development
of AD. The aim of the present study was to examine acetylation of histone H4 at lysine 12
(H4K12) in monocytes in two transgenic AD mouse models (the triple transgenic 3xTg and a model
overexpressing amyloid-precursor protein APP with the Swedish-Dutch-Iowa mutations), and to compare
with monocytes isolated from human patients with mild cognitive impairment (MCI) and AD. Methods: Mouse and
human monocytes were selectively isolated with a positive (PluriSelect) respectively with a negative selection method
(Miltenyi). Histones were extracted and acetylation of H4K12 was analyzed by a quantification fluorometric kit. Moreover,
monocyte cytokine release was measured and cell death analyzed by FACS using incorporation of 7-AAD. Results:
Our data show a significant increase of monocytic H4K12 acetylation in both transgenic AD mouse models early during
development of the plaque deposition in the brain. In line with these data we found significantly elevated acetylation of
H4K12 in human patients with MCI but not in patients with AD. Further we observed that the monocytes of AD mice and
of AD patients were significantly more vulnerable to cell damage (as seen by 7-AAD incorporation in FACS analysis) and
displayed an enhanced release of pro-inflammatory cytokines (MIP2 and TNFα). Conclusion: Our findings indicate that
epigenetic changes in peripheral monocytes are an early event in AD-pathology. Thus H4K12 acetylation may be considered
as a novel biomarker for early changes in AD development.

Abstract:Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by
amyloid-β (Aβ) plaque formation, tau pathology, neurodegeneration and inflammatory processes.
Monocytes are involved in inflammation in AD and are recruited to the diseased brain. Recently it has
been shown that aberrant epigenetic processes including acetylation are associated with the development
of AD. The aim of the present study was to examine acetylation of histone H4 at lysine 12
(H4K12) in monocytes in two transgenic AD mouse models (the triple transgenic 3xTg and a model
overexpressing amyloid-precursor protein APP with the Swedish-Dutch-Iowa mutations), and to compare
with monocytes isolated from human patients with mild cognitive impairment (MCI) and AD. Methods: Mouse and
human monocytes were selectively isolated with a positive (PluriSelect) respectively with a negative selection method
(Miltenyi). Histones were extracted and acetylation of H4K12 was analyzed by a quantification fluorometric kit. Moreover,
monocyte cytokine release was measured and cell death analyzed by FACS using incorporation of 7-AAD. Results:
Our data show a significant increase of monocytic H4K12 acetylation in both transgenic AD mouse models early during
development of the plaque deposition in the brain. In line with these data we found significantly elevated acetylation of
H4K12 in human patients with MCI but not in patients with AD. Further we observed that the monocytes of AD mice and
of AD patients were significantly more vulnerable to cell damage (as seen by 7-AAD incorporation in FACS analysis) and
displayed an enhanced release of pro-inflammatory cytokines (MIP2 and TNFα). Conclusion: Our findings indicate that
epigenetic changes in peripheral monocytes are an early event in AD-pathology. Thus H4K12 acetylation may be considered
as a novel biomarker for early changes in AD development.